Impact of α-targeted radiation therapy on gene expression in a pre-clinical model for disseminated peritoneal disease when combined with paclitaxel.

Abstract

To better understand the molecular basis of the enhanced cell killing effected by the combined modality of paclitaxel and ²¹²Pb-trastuzumab (Pac/²¹²Pb-trastuzumab), gene expression in LS-174T i.p. xenografts was investigated 24 h after treatment. Employing a real time quantitative PCR array (qRT-PCR array), 84 DNA damage response genes were quantified. Differentially expressed genes following therapy with Pac/²¹²Pb-trastuzumab included those involved in apoptosis (BRCA1, CIDEA, GADD45α, GADD45γ, GML, IP6K3, PCBP4, PPP1R15A, RAD21, and p73), cell cycle (BRCA1, CHK1, CHK2, GADD45α, GML, GTSE1, NBN, PCBP4, PPP1R15A, RAD9A, and SESN1), and damaged DNA repair (ATRX, BTG2, EXO1, FEN1, IGHMBP2, OGG1, MSH2, MUTYH, NBN, PRKDC, RAD21, and p73). This report demonstrates that the increased stressful growth arrest conditions induced by the Pac/²¹²Pb-trastuzumab treatment suppresses cell proliferation through the regulation of genes which are involved in apoptosis and damaged DNA repair including single and double strand DNA breaks. Furthermore, the study demonstrates that ²¹²Pb-trastuzumab potentiation of cell killing efficacy results from the perturbation of genes related to the mitotic spindle checkpoint and BASC (BRCA1-associated genome surveillance complex), suggesting cross-talk between DNA damage repair and the spindle damage response.

• Authors: Kwon Joong Yong, Diane E Milenic, Kwamena E Baidoo, Martin W Brechbiel
• Journal: PloS one (PLoS One) Vol. 9 Issue 9 Pg. e108511 ( 2014) ISSN: 1932-6203 [Electronic] United States
• PMID: 25268703 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents
• Apoptosis Regulatory Proteins
• Cell Cycle Proteins
• Lead Radioisotopes
• DNA Repair Enzymes
• Trastuzumab
• Paclitaxel

Topics

• Animals
• Antibodies, Monoclonal, Humanized (pharmacology)
• Antineoplastic Agents (pharmacology)
• Apoptosis Regulatory Proteins (genetics, metabolism)
• Cell Cycle Proteins (genetics, metabolism)
• Colonic Neoplasms (genetics, metabolism, pathology, therapy)
• Combined Modality Therapy
• DNA Breaks, Double-Stranded (drug effects, radiation effects)
• DNA Breaks, Single-Stranded (drug effects, radiation effects)
• DNA Repair Enzymes (genetics, metabolism)
• Drug Evaluation, Preclinical
• Female
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Humans
• Injections, Intraperitoneal
• Lead Radioisotopes
• Mice
• Mice, Nude
• Oligonucleotide Array Sequence Analysis
• Paclitaxel (pharmacology)
• Peritoneal Neoplasms (genetics, metabolism, pathology, therapy)
• Radioimmunotherapy (methods)
• Trastuzumab
• Xenograft Model Antitumor Assays